Regulation of REV-ERBalpha and REV-ERBbeta function of HEME

与碳水化合物和脂质的异常代谢相关的代谢性疾病是导致糖尿病的原因。 在西方社会，老年人的发病率和死亡率都很高。核武器的几个成员 受体超家族调节参与糖和脂质调节的关键基因的表达 代谢响应于它们的配体，其包括脂肪酸、胆汁酸、胆固醇代谢物、类固醇 激素和亲脂性维生素衍生物。最近，一对相关孤儿核激素的配体 调节脂质代谢的受体，rev-erb？还有rev-erb被确认了长期目标是 确定该配体，卟啉血红素，在调节REV-ERBS活性中的作用。我们 组织假设是：血红素是一个关键的配体调节rev-erb？/？基因调控功能 通过调节受体对辅阻遏物的亲和力来调节脂质代谢和分化。假设将 具体目标1将确定血红素对rev-erb的影响 辅阻遏物的募集和转录及分化的调节。具体目标2将决定 血红素对rev-erb的特异性？/ rev-erb？使用生物化学和基于细胞的方法。第3章将 确定血红素是否被用作向REV-ERB传送营养状态信息的传感器 调节参与脂质代谢和脂肪形成的关键基因的表达。这些研究至关重要 对于我们理解配体如何协调REV-ERB调节的代谢，以及更普遍地， 代谢途径受外部环境如营养状况的调节。由于核激素 特征为配体调节的受体已明确显示为有效靶点， 药物开发，我们预测，我们提出的研究可能提供新的基础 靶向rev-erb的治疗方法还有rev-erb用于治疗代谢紊乱。与碳水化合物和脂质的异常代谢相关的代谢性疾病是导致糖尿病的原因。 在西方社会，老年人的发病率和死亡率都很高。我们建议描述一个 新的配体，卟啉血红素，在调节rev-erb？还有rev-erb ?双孤儿核激素 调节脂质代谢关键基因表达的受体。由于核激素 特征为配体调节的受体已明确显示为有效靶点， 药物开发，我们预测，我们提出的研究可能提供新的基础 靶向rev-erb的治疗方法还有rev-erb用于治疗代谢紊乱。

Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. Several members of the nuclear receptor superfamily regulate the expression of key genes involved in regulation of carbohydrate and lipid metabolism in response to their ligands, which include fatty acids, bile acids, cholesterol metabolites, steroid hormones, and lipophilic vitamin derivatives. Recently, the ligand for a pair of related orphan nuclear hormone receptors that regulate lipid metabolism, rev-erb? and rev-erb?, was identified. The long term objective is to determine the role of this ligand, the porphyrin heme, in regulation of the activity of the rev-erbs. Our organizing hypothesis is: heme is a key ligand regulating rev-erb?/? function in regulation of genes controlling lipid metabolism and differentiation by modulating the receptors' affinity for corepressors. The hypothesis will be tested in the following specific aims: Specific Aim 1 will determine the effect of heme on rev-erb corepressor recruitment and regulation of transcription and differentiation. Specific Aim 2 will determine the specificity of heme for rev-erb?/rev-erb? using biochemical and cell-based approaches. Specific Aim 3 will determine if heme is utilized as a sensor conveying nutritional status information to rev-erbs so that they may adjust the expression key genes involved in lipid metabolism and adipogenesis. These studies are essential for our understanding how ligands may coordinate rev-erb regulated metabolism, and more generally, how metabolic pathways are regulated by the external environment such as nutrient status. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb? and rev-erb? for treatment of metabolic disorders. Metabolic diseases associated with aberrant metabolism of carbohydrates and lipids are the cause of significant morbidity and mortality in older people in Western Society. We propose to characterize the role of a novel ligand, the porphyrin heme, in regulation of rev-erb? and rev-erb? ? two orphan nuclear hormone receptors that regulate the expression of key genes involved in lipid metabolism. Since nuclear hormone receptors characterized as ligand-regulated have been definitively shown to be effective targets for the development of pharmaceuticals, we predict that our proposed studies may provide the basis for novel therapeutics targeting rev-erb? and rev-erb? for treatment of metabolic disorders.